Curative-Intent Treatment with Durvalumab in Early-Stage Cancers

Abstract

The introduction of immunotherapy has fundamentally transformed the treatment landscape in cancer, providing long-term survival benefit for patients with advanced disease across multiple tumor types, including nonsmall cell lung cancer (NSCLC). In the placebocontrolled phase 3 PACIFIC trial, the PD-L1 inhibitor durvalumab demonstrated significant improvements in progression-free survival and overall survival in patients with unresectable, stage III NSCLC who had not progressed after platinum-based chemoradiotherapy (CRT). These findings have led to the widespread acceptance of the 'PACIFIC regimen'(durvalumab after CRT) as the standard of care in this setting. Moreover, the PACIFIC trial is the first study to demonstrate a proven survival advantage with an immunotherapy in a curative-intent setting, thereby providing a strong rationale for further investigation of durvalumab in early-stage cancers. Herein, we describe the extensive clinical development program for durvalumab across multiple tumor types in curative-intent settings, outlining the scientific rationale(s) for its use and highlighting the innovative research (e.g., personalized cancer monitoring) advanced by these trials.

Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer

“… 27 Finally, because PACIFIC was the first trial to show a survival advantage with an immunotherapy in a curative-intent setting, it established the rationale for further investigation of durvalumab in other curative-intent settings across other cancers. 27 …”

“…26 Given the unprecedented nature of the findings with the PACIFIC regimen, studies have been initiated to investigate the use of durvalumab after sequential CRT or radiotherapy alone (for patients who are chemotherapy-ineligible), and durvalumab in combination with novel anticancer agents post-CRT, with the aim of further extending clinical benefit to more patients in this setting. 27 In addition, a placebocontrolled, phase III study is investigating durvalumab administered concurrently with CRT (followed by consolidative durvalumab). 27 Finally, because PACIFIC was the first trial to show a survival advantage with an immunotherapy in a curative-intent setting, it established the rationale for further investigation of durvalumab in other curative-intent settings across other cancers.…”

“…27 In addition, a placebocontrolled, phase III study is investigating durvalumab administered concurrently with CRT (followed by consolidative durvalumab). 27 Finally, because PACIFIC was the first trial to show a survival advantage with an immunotherapy in a curative-intent setting, it established the rationale for further investigation of durvalumab in other curative-intent settings across other cancers. 27 In conclusion, these updated survival analyses demonstrate robust and sustained survival benefit with durvalumab after CRT.…”

Role of Ezrin/Radixin/Moesin in the Surface Localization of Programmed Cell Death Ligand-1 in Human Colon Adenocarcinoma LS180 Cells

“…The disruption of the PD-1/PD-L1 interaction by immune checkpoint therapeutic antibodies (Abs) against PD-1 and PD-L1 reactivates antitumor T-cells, resulting in an antitumor effect [ 12 ]. Despite the great success of immune checkpoint therapies blocking the PD-1/PD-L1 interaction in a small subset of various cancer patients [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ], the treatment failed in most cases, including in CRC patients, due to intrinsic unresponsiveness and/or acquired resistance [ 21 , 22 , 23 , 24 , 25 , 26 ]. Specifically, the early clinical trials demonstrated that patients with CRC appeared to be poor responders to immune checkpoint therapies [ 27 , 28 , 29 ], indicating an urgent need for novel immunotherapeutic strategies against CRC.…”

Ezrin Modulates the Cell Surface Expression of Programmed Cell Death Ligand-1 in Human Cervical Adenocarcinoma Cells

“…Immune checkpoint blockade (ICB) therapy targeting the PD-L1 (e.g., atezolizumab, avelumab, and durvalumab)/PD-1 (e.g., nivolumab, pembrolizumab, Molecules 2021, 26, 5648 2 of 22 spartalizumab, and cemiplimab) axis reactivates T-cell immunity in tumor microenvironment [12]. In recent decades, the introduction of ICB therapy has fundamentally transformed the treatment landscape in various types of advanced cancers, including cervical cancer, and provided long-term survival benefits [3,[12][13][14][15][16]. On the other hands, less than 40% of patients derive clinical benefits because many cancer patients are primary and/or adaptive resistance to immune checkpoint inhibitors [17][18][19][20][21][22].…”